Asymmetric synthesis of pregabalin

ABSTRACT

This invention provides a method of making (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid (pregabalin) or a salt thereof via an asymmetric hydrogenation synthesis. Pregabalin is useful for the treatment and prevention of seizure disorders, pain, and psychotic disorders. The invention also provides intermediates useful in the production of pregabalin.

FIELD OF THE INVENTION

[0001] This invention relates to a method of making(S)-(+)-3-(aminomethyl)-5-methylhexanoic acid (pregabalin) in anasymmetric synthesis. Pregabalin is useful for the treatment andprevention of seizure disorders, pain, and psychotic disorders.

BACKGROUND OF THE INVENTION

[0002] (S)-(+)-3-(Aminomethyl)-5-methylhexanoic acid is knowngenerically as pregabalin. The compound is also called(S)-(+)-β-isobutyl-γ-aminobutyric acid, (S)-isobutyl-GABA, and CI-1008.Pregabalin is related to the endogenous inhibitory neurotransmitterγ-aminobutyric acid or GABA, which is involved in the regulation ofbrain neuronal activity. Pregabalin has anti-seizure activity, asdescribed by Silverman et al., U.S. Pat. No. 5,563,175. Otherindications for pregabalin are also currently being pursued (see, forexample. Guglietta et al., U.S. Pat. No. 6,127,418, and Singh et al.,U.S. Pat. No. 6,001,876).

[0003] A seizure is defined as excessive unsynchronized neuronalactivity that disrupts normal brain function. It is thought thatseizures can be controlled by regulating the concentration of the GABAneurotransmitter. When the concentration of GABA diminishes below athreshold level in the brain, seizures result (Karlsson et al., Biochem.Pharmacol. 1974:23:3053); when the GABA level rises in the brain duringconvulsions, the seizures terminate (Havashi. Physiol. (London),1959;145:570).

[0004] Because of the importance of GABA as a neurotransmitter, and itseffect on convulsive states and other motor dysfunctions, a variety ofapproaches have been taken to increase the concentration of GABA in thebrain. In one approach, compounds that activate L-glutamic aciddecarboxylase (GAD) have been used to increase the concentration ofGABA, as the concentrations of GAD and GABA vary in parallel, andincreased GAD concentrations result in increased GABA concentrations(Janssens de Varebeke et al., Biochem. Pharmacol, 1983;32:2751; Loscher,Biochem. Pharmacol. 1982;31:837; Phillips et al., Biochem. Pharmacol.,1982;31:2257). For example, the racemic compound(±)-3-(aminomethyl)-5-methylhexanoic acid (racemic isobutyl-GABA), whichis a GAD activator, has the ability to suppress seizures while avoidingthe undesirable side effect of ataxia.

[0005] The anticonvulsant effect of racemic isobutyl-GABA is primarilyattributable to the S-enantiomer (pregabalin). That is, the S-enantiomerof isobutyl-GABA shows better anticonvulsant activity than theR-enantiomer (see, for example, Yuen et al., Bioorganic & MedicinalChemistry Letters, 1994;4:823). Thus, the commercial utility ofpregabalin requires an efficient method for preparing the S-enantiomersubstantially free of the R-enantiomer.

[0006] Several methods have been used to prepare pregabalin. Typically,the racemic mixture is synthesized and then subsequently resolved intoits R- and S-enantiomers (see U.S. Pat. No. 5,563,175 for synthesis viaan azide intermediate). Another method uses potentially unstable nitrocompounds, including nitromethane, and an intermediate that is reducedto an amine in a potentially exothermic and hazardous reaction. Thissynthesis also uses lithium bis(trimethylsilylamide) in a reaction thatmust be carried out at −78° C. (Andruszkiewicz et al., Synthesis,1989:953). More recently, the racemate has been prepared by a “malonate”synthesis, and by a Hofmann synthesis (U.S. Pat. Nos. 5,840,956;5,637,767; 5,629,447; and 5,616,793). The classical method of resolvinga racemate is used to obtain pregabalin according to these methods.Classical resolution involves preparation of a salt with a chiralresolving agent to separate and purify the desired S-enantiomer. Thisinvolves significant processing, and also substantial additional costassociated with the resolving agent. Partial recycle of the resolvingagent is feasible, but requires additional processing and cost, as wellas associated waste generation. Moreover, the undesired R-enantiomercannot be efficiently recycled and is ultimately discarded as waste. Themaximum theoretical yield of pregabalin is thus 50%, since only half ofthe racemate is the desired product. This reduces the effectivethroughput of the process (the amount that can be made in a givenreactor volume), which is a component of the production cost andcapacity.

[0007] Pregabalin has been synthesized directly via several differentsynthetic schemes. One method includes use of n-butyllithium at lowtemperatures (≦35° C.) under carefully controlled conditions. Thissynthetic route requires the use of(4R,5S)-4-methyl-5-phenyl-2-oxazolidinone as a chiral auxiliary tointroduce the stereochemical configuration desired in the final product(U.S. Pat. No. 5,563,175). Thus, although these general strategiesprovide the target compound in high enantiomeric purity, they are notpractical for large-scale synthesis because they employ costly reagentswhich are difficult to handle, as well as special cryogenic equipment toreach the required operating temperatures.

[0008] Because pregabalin is being developed as a commercialpharmaceutical product, the need exists for an efficient, costeffective, and safe method for its large-scale synthesis. In order to beviable for commercial manufacturing, such a process needs to be highlyenantioselective, for example, where the product is formed with asubstantial excess of the correct enantiomer. An object of thisinvention is to provide such a process, namely an asymmetrichydrogenation process.

[0009] Asymmetric hydrogenation processes are known for some compounds.Burk et al., in WO 99131041 and WO 99/52852, describe asymmetrichydrogenation of β-substituted and β,β-disubstituted itaconic acidderivatives to provide enantiomerically enriched 2-substituted succinicacid derivatives. The itaconic substrates possess two carboxyl groups,which provide the requisite steric and electronic configuration todirect the hydrogenation to produce a %n enriched enantiomer. Thedisclosures teach that salt forms of the formula RR C═C(CO₂Me)CH₂CO₂—Y⁺are required to obtain hydrogenated products having at least 95%enantiomeric excess.

[0010] According to U.S. Pat. No. 4,939,288, asymmetric hydrogenationdoes not work well on substrates having an isobutvl group. We have nowdiscovered that an isobutyl cyano carboxy acid, salt or ester substrate,of the formula iPrCH═C(CN)CH₂CO)R, can be selectively hydrogenated toprovide an enantiomerically enriched nitrile derivative, which can besubsequently hydrogenated to produce substantially pure pregabalin. Thisselectivity is particularly surprising given the dramatic differences insteric configuration and inductive effects of a nitrile moiety comparedto a carboxy group. Indeed, there is no teaching in the prior art of thesuccessful asymmetric hydrogenation of any cyano substituted carboxyolefin of this type.

SUMMARY OF THE INVENTION

[0011] The present invention provides an efficient method of preparing(S)-3-(aminomethyl)-5-methylhexanoic acid (pregabalin). The methodcomprises asymmetric hydrogenation of a cyano substituted olefin toproduce a cyano precursor of (S)-3-(aminomethyl)-5-methylhexanoic acid.The method further comprises a reaction to convert the cyanointermediate into (S)-3-(aminomethyl)-5-methylhexanoic acid. Theasymmetric synthesis of (S)-3-(aminomethyl)-5-methylhexanoic aciddescribed herein results in a substantial enrichment of pregabalin overthe undesired (R)-3-(aminomethyl)-5-methylhexanoic acid. TheR-enantiomer is produced only as a small percentage of the finalproduct.

[0012] The present invention offers several advantages over previousmethods of making pregabalin. For example, processing to remove theundesired R-enantiomer and subsequent disposal of this waste isminimized. Because the S-enantiomer is greatly enriched in the finalproduct, the asymmetric approach is more efficient. Furthermore, thepresent method does not require the use of hazardous nitro compounds,costly chiral auxiliaries, or low temperatures as required in previousmethods. Moreover, unlike the classical resolution approaches or thechiral auxiliary route, which require stoichiometric amounts of thechiral agent, this synthesis utilizes sub-stoichiometric quantities ofthe chiral agent as a catalyst. Thus, the method of the presentinvention has both economic and environmental advantages.

DETAILED DESCRIPTION OF THE INVENTION

[0013] As used herein, the term “lower alkyl” or “alkyl” means astraight or branched hydrocarbon having from 1 to 6 carbon atoms andincludes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like.

[0014] The term “aryl” means an aromatic carbocyclic group having asingle ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiplecondensed rings in which at least one is aromatic (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl). The arylgroup may be unsubstituted or substituted by 1 to 3 substituentsselected from alkyl, O-alkyl and S-alkyl, OH, SH, —CN, halogen,1,3-dioxolanyl, CF₃, NO₂, NH₂, NHCH₃, N(CH₃)₂, NHCO-alkyl,—(CH₂)_(m)CO₂H, —(CH₂)_(m)CO₂-alkyl, —(CH₂)_(m)SO₃H, —NH alkyl,—N(alkyl)₂, —CH₂)_(m)PO₃H₂, —(CH₂)_(m)PO₃(alkyl)₂, —(CH₂)_(m)SO₂NH₂, and—(CH₂)_(m)SO₂NH-alkyl, wherein alkyl is defined as above and m is 0, 1,2, or 3. A preferable aryl group of the present invention is phenyl.Typical substituted aryl groups include methylphenyl, 4-methoxybiphenyl,3-chloronaphth-1-yl, and dimethylaminophenyl.

[0015] The term “arylalkyl” means an alkyl moiety (as defined above)substituted with an aryl moiety (also as defined above). Examplesinclude benzyl and 2-naphthlethyl.

[0016] The disclosures in this application of all articles andreferences, including patents, are incorporated herein by reference.

[0017] The present invention provides an efficient synthesis of(S)-3-(aminomethyl)-5-methylhexanoic acid (pregabalin). This synthesisis depicted in Scheme 1, below,

[0018] wherein R¹ is lower alkyl, aryl, arylalkyl or allyl; and Y is acation, and preferably H⁺, the salt of a primary or secondary amine, analkaline earth metal, such as tert-butyl ammonium, or an alkali metalsuch as sodium.

[0019] As illustrated in Scheme 1, a metal salt 2 (where Y is potassium,for example) of a cyano alkanoic acid may be obtained from the cyanohexenoate ester 1a or 1b by sequential asymmetric hydrogenation andester hydrolysis to the free acid or salt. Subsequent reduction of thenitrile 2 by routine hydrogenation with a catalyst such as nickel,followed by acidification of the carboxylate salt, affords pregabalin.Alternatively, these steps can be reversed, such that the substrate forasymmetric hydrogenation is the acid or salt 4

[0020] where X is CO₂H or CO₂—Y, and Y is a cation. Compound 4 can existas the individual E or Z geometric isomer, or a mixture thereof. Saltscan be formed by reacting the free acid (X is CO₂H) with a strong basesuch as a metal hydroxide, e.g., KOH. Alternatively, the salt may beformed with, for example, a counterion WH+ such as that derived from anamine (W) or a phosphine (W). Primary C₁₋₁₀ alkylamines andcycloalkylamines are preferred, in particular, tert-butylamine. Tertiaryamines such as triethylamine may also be used. Again, subsequentreduction of the nitrile 2 by standard methods, followed byacidification of the carboxylate salt, affords pregabalin.

[0021] In the general synthesis of pregabalin according to Scheme 1, thecyano olefin compound 1a or 1b undergoes ester hydrolysis and asymmetrichydrogenation to form the desired enantiomer of a3-cyano-5-methylhexanoic acid or the corresponding carboxylate salt 2.The olefin substrate can be the individual E or Z geometric isomer, or amixture thereof. Subsequent reduction of the nitrile 2, followed byacidification of the carboxylate salt, affords pregabalin.

[0022] The asymmetric hydrogenation step is performed in the presence ofa chiral catalyst, preferably a rhodium complex of an (R,R)-DuPHOS or(S,S)-DuPHOS ligand, commercially available from Strem Chemicals, Inc.(7 Mulliken Way, Newburyport, Mass. 01950-4098) and Chirotech TechnologyLimited (Cambridge Science Park, Cambridge, Great Britain) (see U.S.Pat. Nos. 5,532,395 and 5,171,892). The ligand preferably has theformula

[0023] wherein R is lower alkyl. Preferred alkyl groups for R aren-alkyl groups, such as, for example, methyl, ethyl, propyl, butyl,pentyl or hexyl. More preferred alkyl groups for R are methyl or ethyl.Other catalysts that can be used include rhodium complexes of chiral-BPEand chiral-DIPAMP which have the formulas

[0024] Such catalysts generally are complexed with 1,5-cyclooctadiene(COD). These agents are fully described by Burk et al. in J. Am. Chem.Soc., 1995;117:9375.

[0025] The asymmetric hydrogenation reaction is carried out under ahydrogen atmosphere and preferably in a protic solvent such as methanol,ethanol, isopropanol, or a mixture of such alcohols with water.

[0026] The cyano hexenoate starting materials (e.g., 1a) are readilyavailable (Yamamoto et al. Bull. Chem. Soc. Jap., 1985;58:3397). Theycan be prepared according to Scheme 2, below,

[0027] wherein R¹ is as defined above in Scheme 1 and R² is COCH₃ orCO₂alkyl.

[0028] In the synthesis of a compound 1a according to Scheme 2, aminecatalyzed addition of acrylonitrile (i.e., the Baylis-Hillman reaction)to 2-methylpropanal affords the cyano allylic alcohol. Typical aminesused to catalyze the condensation include agents such as1,4-diazabicyclo[2,2,2]octane (Dabco). The cyano allylic alcohol issubsequently converted to either an alkyl carbonate (e.g., by reactionwith an alkyl halo formate such as ethyl chloro formate) or therespective acetate (by reaction with acetic anhydride or acetylchloride). The resulting 2-(2-methylpropyl)prop-2-enenitrile is thensubjected to palladium-catalyzed carbonylation to produce ethyl3-cyano-5-methylhex-3-enoate 1a (e.g., where R¹ is methyl or ethyl).

[0029] In one embodiment of the invention illustrated in Scheme 3 below,asymmetric hydrogenation is first carried out on 1a (where R¹ is ethylfor example) to form the (S)-3-cyano-5-ethylhexanoic acid ester 3. Useof chiral (S,S) hydrogenation catalysts from the bisphospholane series,for example [(S,S)-Me-DuPHOS]Rh(COD)⁺BF₄ ⁻ on the ester substrates(e.g., R¹ is alkyl) provides products enriched in the desiredS-enantiomer. The ester 3 is subsequently hydrolyzed to the acid or salt2. Scheme 3 below shows this synthetic route. wherein Y is as definedabove for Scheme 1. By switching to the catalyst[(R,R)-Me-DuPHOS]Rh(COD)⁺BF₄ ⁻, the hydrogenation product is enriched in(R)-3-cyano-5-methylhexanoic acid ethyl ester. Typically, thesehydrogenation processes provide for substrate conversion of at least90%. and enantiomeric enrichment (e.e.) of 20% to 25%. Furtherenrichment of the product can be effected by selective recrystallizationwith a chiral resolving agent. as described below.

[0030] A preferred embodiment of the invention is illustrated in Scheme4. where the ester 1a is first hydrolyzed to the salt of the 3-hexenoicacid 4, (e.g., 4a as shown in Scheme 4 where Y is sodium or potassium).The cyano hexanoic acid salt 4a is then hydrogenated to the salt 2. Thecyano hexanoic acid salt 4a may be isolated, or may be prepared in situprior to hydrogenation. Scheme 4 below depicts this preferredembodiment, wherein Y is as defined above for Scheme 1. A distinctivefeature of the hydrogenation of the salt 4a is that the desiredS-enantiomer 2 is obtained by use of a chiral (R,R) catalyst from thebisphospholane series, for example [(R,R)-Me-DuPHOS]Rh(COD)⁺BF₄ ⁻. Thisrepresents an unexpected switch in absolute stereochemistry whencompared to hydrogenation of the ester substrate 1a (Scheme 3). Inaddition, the enantioselectivity achieved in the hydrogenation of thesalt 4a is much higher, typically at least about 95% e.e. The choice ofcation Y does not appear to be critical, since comparableenantioselectivities are observed with metallic cations (e.g., K⁺) andnon-metallic cations (e.g., tert-butyl ammonium). Without being bound bytheory, the contrasting properties of substrates 1a and 4a may derivefrom binding interactions between functional groups of each substrateand the rhodium center in the catalyst, which in turn may influence boththe direction and degree of facial selectivity during hydrogenation ofthe olefin. Thus, in the hydrogenation of the ester 1a, the cyanosubstituent may participate in binding to the catalyst. This effectappears to be entirely overridden in hydrogenation of the salt 4a, inwhich binding by the carboxylate group is likely to be dominant.

[0031] As a further embodiment, the invention provides novel compoundsof the formula 4

[0032] wherein X is CO₂H or CO₂—Y, and where Y is a cation as describedabove in Scheme 1. These compounds are useful substrates in thesynthesis of pregabalin.

[0033] In another preferred embodiment of the invention. the finalpregabalin product may be selectively recrystallized with (S)-mandelicacid to provide still further enhanced enrichment of the desiredS-isomer. Thus, high levels of the (R)-enantiomer (up to at least 50%)can be removed by classical resolution via the S-mandelic acid salt(U.S. Pat. No. 5,840,956; U.S. Pat. No. 5,637,767). Suitable solventsfor such selective recrystallizations include, for example, water or analcohol (e.g., methanol, ethanol, and isopropanol, and the like) or amixture of water and an alcohol. In general, excess mandelic acid isused. It is also noted that mandelic acid can be used in combinationwith another acid.

[0034] Alternatively, pregabalin containing low levels (<1%) of the(R)-enantiomer, can be enriched to >99.9% of the (S)-enantiomer bysimple recrystallization from, for example. water/isopropyl alcohol.Pregabalin containing higher levels (up to 3.5%) of the (R)-enantiomer),can also be enriched by simple recrystallization from. for example,water/isopropyl alcohol, although successive recrystallizations areusually required to reach >99.9% of the (S)-enantiomer. “Substantiallypure” pregabalin, as used herein. means at least about 95% (by weight)S-enantiomer, and no more than about 5% R-enantiomer.

[0035] The following detailed examples further illustrate particularembodiments of the invention. These examples are not intended to limitthe scope of the invention and should not be so construed. The startingmaterials and various intermediates may be obtained from commercialsources, prepared from commercially available compounds, or preparedusing well-known synthetic methods well-known to those skilled in theart of organic chemistry.

[0036] Preparations of Starting Materials

[0037] 3-Hydroxy-4-methyl-2-methylene Pentanenitrile

[0038] A 250 mL, three-necked. round-bottom flask with overhead stirringis charged with 0.36 g (1.6 mmol) of 2,6-di-tert-butyl-4-methylphenol,37 g (0.33 mol) of 1,4-diazabicyclo[2,2,2]octane, 60 mL (0.66 mol) ofisobutyraldehyde, 52 mL (0.79 mol) of acrylonitrile, and 7.2 mL (0.4mol) of water. The reaction mixture is stirred at 50° C. for 24 hours,cooled to 25° C., and quenched into a solution of 33 mL (0.38 mol) ofhydrochloric acid and 100 mL of water. The product is extracted with 120mL of methylene chloride. The aqueous acid layer is extracted again with25 mL of methylene chloride. The combined methylene chloride layers areconcentrated by rotary evaporation to provide 79.9 g (96.7%) of3-hydroxy-4-methyl-2-methylenepentanenitrile as a yellow oil (which maysolidify to a white solid on standing), 96.7% (area under the curve) byHPLC assay, which may be used in the next step without furtherpurification.

[0039] Carbonic Acid 2-cyano-1-isopropyl-allyl Ester Ethyl Ester

[0040] A nitrogen-purged 5 L, three-necked, round-bottom flask withoverhead stirring is charged with 150 g (1.2 mol) of3-hydroxy-4-methyl-2-methylenepentanenitrile, 1.0 L of methylenechloride. and 170 mL (2.1 mol) of pyridine. The solution is cooled at10° C. to 15° C. in an ice bath. Using a 1 L graduated addition funnel.a mixture of 0.5 L of methylene chloride and 200 mL (2.1 mol) of ethylchloroformate is added slowly while maintaining the reaction temperatureat 20° C.±5° C. The reaction is stirred at 22° C.±3° C. for about twoadditional hours. The reaction solution is poured into a 6 L separatoryfunnel containing 200 mL (2.3 mol) of hydrochloric acid and 1.25 L ofwater. The lower organic layer is washed again with a solution of 60 mL(0.7 mol) of HCl and 0.5 L of water. The organic layer is dried overanhydrous magnesium sulfate (30 g), filtered, and concentrated by rotaryevaporation to provide 226 g of carbonic acid 2-cyano-1-isopropyl-allylester ethyl ester as a yellow oil which may be used in the next stepwithout further purification.

[0041] Acetic Acid 2-cyano-1-isopropyl-allyl Ester (Using AcetylChloride)

[0042] A nitrogen-purged 5 L, three-necked. round-bottom flask withoverhead stirring is charged with 50 g (0.4 mol) of3-hydroxy-4-methyl-2-methylenepentanenitrile, 0.4 L of methylenechloride, and 80 mL (1 mol) of pyridine. The solution is cooled at 10°C. to 15° C. in an ice bath. Using a 500 mL graduated addition funnel, amixture of 100 mL of methylene chloride and 43 mL (0.6 mol) of acetylchloride is added slowly while maintaining the reaction temperature at25° C.±5° C. The reaction is stirred at 22° C. ±3° C. for about oneadditional hour. The reaction solution is poured into a 4 L separatorsfunnel containing 85 mL (1.0 mol) of hydrochloric acid and 750 mL ofwater. The lower organic layer is washed again with a solution of 20 mL(0.2 mol) of HCl and 250 mL of water. The organic layer is dried overanhydrous magnesium sulfate (20 g), filtered, and concentrated by rotaryevaporation to provide 66 g of acetic acid 2-cyano-1-isopropyl-allylester as a yellow oil which may be used in the next step without furtherpurification.

[0043] Acetic Acid 2-cyano-1-isopropyl-allyl Ester (Using AceticAnhydride)

[0044] To a 500 mL, four-necked, round-bottom flask equipped with anoverhead stirrer, a temperature probe, a reflux condenser. and anitrogen inlet is charged acetic anhydride (40 mL, 0.45 mol). Thissolution is heated to 50° C. and a solution of3-hydroxy-4-methyl-2-methylenepentanenitrile (50 g, 0.40 mol) and4-(dimethylamino)pyridine (1.5 g) in tetrahydrofuran (25.mL) is addedover 35 minutes. A temperature of 50° C. to 63° C. is maintained withoutexternal heating. After the addition is complete, the reaction mixtureis heated at 60° C. for 75 minutes. The solution is cooled to 30° C. andthe cooled reaction mixture is diluted with 30 mL of tert-butylmethylether (MTBE) and 25 mL of water. This mixture is cooled to 10° C. and asolution of 50% aqueous sodium hydroxide (37 g, 0.46 mol) diluted with45 mL of water is added with cooling, such that the temperature ismaintained at about 15° C. For the final pH adjustment, 50% aqueoussodium hydroxide 9.8 g (0.12 mol) is added dropwise to a final pH of9.4. After adding 10 mL of water and 10 to 15 mL of MTBE, the reactionmixture is phased and separated. The upper organic product layer isseparated and washed with 25 mL of brine. dried over magnesium sulfate.and concentrated in vacuo to provide 63.7 g (95%) of acetic acid2-cyano-1-isopropyl-allyl ester as a pale yellow oil.

[0045] Ethyl 3-cyano-5-methyl Hex-3-enoate

[0046] A high pressure reactor with overhead stirring is charged with3.0 g (13.4 mmol) of palladium acetate, 7.0 g (26.8 mmol) oftriphenylphosphine, and 226 g (0.92 mol) of the crude oil containingcarbonic acid 2-cyano-1-isopropyl-allyl ester ethyl ester, and 500 mL ofethanol. Carbon monoxide is introduced at 280 to 300 psi, and themixture is heated at 50° C. overnight with stirring. The red-brownsolution is filtered through celite to remove solids. The filtrate isconcentrated by rotary evaporation to provide 165 g of crude yellow oilyproduct, ethyl-3-cyano-5-methyl hex-3-enoate. which assays 84% (area) bygas chromatography (GC) as a mixture of the E and Z geometric isomers.The crude product may be used without further purification. oralternatively. is purified by vacuum distillation (0.6-1.0 mm Hg at 60°C.-70° C.) to give a colorless oil which assays ≧95% (area) by GC.

[0047] Ethyl 3-cyano-5-methyl hex-3-enoate (Using, KBr)

[0048] A high pressure reactor with overhead stirring is charged withpalladium acetate (0.52 g, 2.3 mmol), triphenylphosphine (0.65 g, 2.3mmol), potassium bromide (5.5 g, 4.8 mmol), a crude oil containingcarbonic acid 2-cyano-1-isopropyl-allyl ester ethyl ester (240 g, 1.2mole), triethylamine (2.2 g, 22 mmol), ethanol 2B (45 mL), andacetonitrile (200 mL). Carbon monoxide is introduced at 50 psi. and themixture is heated at 50° C. overnight with stirring. The pressure of thereactor is released to 10 to 15 psi after about 1, 3, and 6 hours and isrefilled with carbon monoxide to 50 psi. The reaction mixture isfiltered through celite to remove solids. The filtrate is concentratedin vacuo and 800 mL of hexane is added. The resulting mixture is washedtwice with 500 mL of water. and the hexane is removed in vacuo toprovide 147 g of crude ethyl 3-cyano-5-methyl hex-3-enoate as an oil.This crude product is purified by fractional distillation (0.7 mm Hg at60° C.-70° C.).

[0049] Ethyl 3-cyano-5-methyl Hex-3-enoate (Using NaBr)

[0050] A high pressure reactor with overhead stirring is charged with0.5 g (0.5 mmol) of tris(dibenzylideneacetone)dipalladium (0), 0.5 g(2.0 mmol) of triphenylphosphine, 0.5 g (5.0 mmol) of sodium bromide,4.5 mL (25.0 mmol) of diisopropylethylamine, 8.35 g (50.0 mmol) ofacetic acid 2-cyano-1-isopropyl-allyl ester, and 100 mL of ethanol.Carbon monoxide is introduced at 40 to 50 psi, and the mixture is heatedat 50° C. for 24 hours with stirring. The brown solution is filteredthrough celite to remove solids. The filtrate is concentrated by rotaryevaporation. The concentrated reaction mixture is diluted with 150 mL ofmethyl tert-butyl ether and washed with water. The solvent is removed ona rotary evaporator to provide 7.7 g of crude yellow oily product,ethyl-3-cyano-5-methyl hex-3-enoate (85 area percent on GC assay). Thecrude product may be used without further purification. oralternatively, may be purified by vacuum distillation (0.6-1.0 mm Hg at60° C.-70° C.).

EXAMPLE 1

[0051] Synthesis of 3-cyano-5-methylhex-3-enoic Acid Salts A.tert-Butylammonium salt of 3-cyano-5-methylhex-3-enoic acid

Material MWt Quantity mmol Ethyl 3-cyano-5-methylhex-3-enoate 181.2420.02 g 110 LiOH H₂O 41.96  13.0 g 310 Tetrahydrofuran   75 mL Water  25 mL Hydrochloric Acid (2N) As required Ethyl Acetate As requiredtert-butylamine 73.14  9.27 g 127

[0052] Ethyl 3-cyano-5-methylhex-3-enoate (mixture of E and Z isomers)and lithium hydroxide hydrate are suspended in a mixture oftetrahydrofuran and water. The slurry is vigorously stirred for 4 hoursat room temperature. The mixture is acidified to pH 2 (3N HCl) andextracted into ethyl acetate (3×150 mL). The combined organic layers aredried (MgSO₄). and the solvent is removed in vacuo to give crude3-cyano-5-methylhex-3-enoic acid. The crude acid is dissolved in ethylacetate (400 mL), and a solution of tert-butylamine in ethyl acetate (20mL) is added. The temperature of the solution rises approximately 10° C.as a mass of white crystalline solid precipitates. The product iscollected by filtration and dried in vacuo. Yield 22.15 g, 97.9 mmol,89%.

[0053] A1. tert-Butyl Ammonium 3-cyano-5-methylhex-3-enoate (AlternativeMethod)

[0054] To an appropriately sized 3-necked round-bottomed flask ischarged 50 g of an oil containing ethyl 3-cyano-5-methylhex-3-enoate(29.9 g contained weight, 165 mmol). A solution of KOH (91%, 10.2 g,165.1 mmol) in 50 mL of water is charged to the ester solution over 20minutes. and the solution is allowed to stir for 1 additional hour.Water (50 mL) is charged. and the solution is concentrated to 80 mL invacuo. The water solution is washed with MTBE (100 mL), and theproduct-containing aqueous layer is acidified to a pH of 1 withconcentrated hydrochloric acid (20 mL). The resulting acid is extractedinto MTBE (100 mL). The product-containing MTBE solution is concentratedin vacuo. The resultant oil is dissolved in isopropyl alcohol (58 mL)and heptane (85 mL), and this solution is filtered through celite. Thefilter cake is washed with a mixture of isopropyl alcohol (58 mL) andheptane (85 mL). tert-Butylamine is charged to the solution to form athick gel-like slurry. The slurry is heated to reflux to give asolution. The solution is allowed to slowly cool to room temperature.The resultant slurry is cooled to 0° C. to 5° C. for 1.5 hours thenfiltered and washed with a mixture of isopropyl alcohol (50 mL) andheptane (150 mL). The solid is dried under vacuum at 45° C. to 50° C. togive 23.1 g (62%) of tert-butyl ammonium 3-cyano-5-methylhex-3-enoate asa white solid which is a mixture of E and Z isomers. The Z isomer can beobtained in greater than 99% isomeric purity by recrystallization fromisopropyl alcohol and heptane. B. Potassium salt of3-cyano-5-methylhex-3-enoic acid

Material Source MWt Quantity mmol Ethyl 3-cyano-5-methylhex- PD61966X130 181.24 90.8 g 501 3-enoate Potassium hydroxide 85% Aldrich56.11 33.1 g 501 Methanol Fisher 90 mL tert-Butylmethyl ether Fisher 900mL

[0055] Potassium hydroxide is dissolved in methanol (70 mL) and added torapidly stirring ethyl 3-cyano-5-methylhex-3-enoate (mixture of E and Zgeometric isomers) at such a rate as to maintain the temperature below45° C.

[0056] The residual methanolic potassium hydroxide is rinsed into themixture with extra methanol (2×10 mL). The mixture is heated at 45° C.for 1 hour and then allowed to cool to room temperature during whichtime a crystalline solid forms. tert-Butylmethyl ether (600 mL) isslowly added to the mixture with vigorous stirring. The solid iscollected on a course frit filter. washed with tert-butylmethyl ether(3×100 mL). and dried to provide the title compound. Yield 83.9 g, 439mmol, 88%.

EXAMPLE 2

[0057] Asymmetric Hydrogenation of 3-cyano-5-methylhex-3-enoic AcidSalts A. tert-Butylammonium salt of (S)-3-cyano-5-methylhexanoic acid

Material MWt Quantity mmol tert-Butylammonium salt of 3-cyano- 226.3319.0 g 84 5-methylhex-3-enoic acid [(R,R)-MeDuPHOS]Rh(COD) BF₄ ⁻ 60449.6 mg 0.082 Methanol 32  200 mL Hydrogen 2  44 psi (3 bar)

[0058] A round-bottom flask is charged with the tert-butylammonium saltof 3-cyano-5-methylhex-3-enoic acid (from Example 1A) and[(R,R)-MeDuPHOS]Rh(COD)⁺BF₄ ⁻ under a nitrogen atmosphere. Deoxygenatedmethanol is added via syringe, and the solution is deoxygenated byrepeated partial evacuation and back filling with nitrogen. A 600 mLPARR pressure vessel is purged with hydrogen by pressurizing andreleasing the pressure three times. The vessel is then heated to 55° C.The solution of substrate and catalyst is transferred to the reactor bycannula, and the vessel is again purged with hydrogen before finallypressurizing to 3 bar (44 psi). Stirring is started and hydrogen up-takecommenced. The vessel is repeatedly recharged to 3 bar pressure untilhydrogen uptake ceases (˜45 min). After stirring under pressure at 55°C. for an additional 1 hour, heating is discontinued. Once the reactorcools to room temperature, the hydrogen pressure is released. the vesselis purged with nitrogen, and the reaction mixture is transferred to around-bottom flask. The solvent is removed in vacuo to give the crudeproduct. A small sample is removed and converted to(S)-3-cyano-5-methylhexanoic acid by treatment with aqueous hydrochloricacid and extraction into dichloromethane. GC analysis shows 100%conversion to the reduced cyano alkane with 95.0% e.e. (S). B. Potassiumsalt of (S)-3-cyano-5-methylhexanoic acid (substrate to catalyst (S/C)ratio 1000/1)

Material MWt Quantity mmol Potassium salt of 3-evano- 191.3 11.03 g 57.75-methylhex-3-enoic acid [(R,R)-MeDuPHOS]Rh(COD) 604 11 mg in 18.2 ×10⁻³ BF₄ ⁻ 10 mL S/C = 1000 ^(W)/_(W) MeOH Methanol 32 100 mL Hydrogen 260 psi (4 bar)

[0059] A glass liner is charged with the potassium salt of3-cyano-5-methylhex-3-enoic acid (from Example 1B) and methanol andplaced in a 600 mL PARR hydrogenation vessel. The vessel is purged withnitrogen and then with hydrogen via charging to 60 psi and stirring for10 minutes to ensure thorough equilibration of gases and releasing ofthe pressure on five cycles. The vessel is heated to 45° C., and asolution of [(R,R)-MeDuPHOS]Rh(COD)BF₄ ⁻ in deoxygenated methanol (11 mgin 10 mL) is added via syringe. The vessel is again purged with hydrogenand then pressurized to 60 psi with stirring. Periodically, hydrogen isadded to maintain the pressure between 50 to 65 psi. Hydrogen uptakeceases after 120 minutes. After 2 hours. the mixture is cooled to roomtemperature. the pressure is released. and the solvent is removed togive the crude product. A small sample is removed and acidified with 1 NHCl to give (S)-3-cyano-5-methylhexanoic acid. GC analysis shows >99%conversion with 96.7% e.e S isomer. C. Potassium salt of(S)-3-cyano-5-methylhexanoic acid (substrate to catalyst (S/C) ratio3200/1,640 mmol)

Material MWt Quantity mmol Potassium 181.2 123 g 6403-cyano-5-methylhex-3-enoate [(R,R)-MeDuPHOS]Rh(COD)⁺BF₄ 604 123 mg0.204 Methanol 32 1015 mL Hydrogen 2 60 psi (4 bar)

[0060] A glass liner was charged with potassium3-cyano-5-methylhex-3-enoate (from Example 1 B) and methanol (1000 mL).The liner was placed in a 2 L PARR hydrogenation vessel. The vessel waspurged with nitrogen and then with hydrogen via charging to 60 psi andreleasing the pressure over five cycles. The vessel was then heated to45° C. A solution of [(.R)-MeDuPHOS]Rh(COD)⁺BF₄ ⁻ in deoxygenatedmethanol (15 mL) was added via syringe. The vessel was again purged withhydrogen three times then pressurized to 65 psi and stirring commenced.Periodically, hydrogen was added to maintain the pressure between 50 to65 psi. Hydrogen uptake ceased after 2½ hours, the vessel was cooled toroom temperature and left to stir overnight. The pressure was released,the mixture was transferred to a flask. and the solvent was removed invacuo to give the product. A small sample was removed and converted tomethyl (S)-3-cyano-5-methylhex-3-enoate. Gas chromatographic analysisshowed >99% conversion 97.5% e.e. D. tert-Butylammonium salt of(S)-3-cyano-5-methylhexanoic acid (S/C ratio 2700/1,557 mmol)

Material MWt Quantity mmol tert-Butylammonium 3-cyano-5- 226.33 125.8 g557 methylhex-3-enoate [(R,R)-MeDuPHOS]Rh(COD)⁺BF₄ ⁻ 604 125 mg 0.082Methanol 32 200 mL Hydrogen 2 50-65 psi

[0061] A glass liner was charged with tert-butylammonium3-cyano-5-methylhex-3-enoate and methanol (1000 mL). The liner wasplaced in a 2 L PARR hydrogenation vessel. The vessel was purged withnitrogen and then with hydrogen via charging to 60 psi and releasing thepressure over five cycles. The vessel was then heated to 45° C. Asolution of [(R,R)-MeDuPHOS]Rh(COD)⁺BF₄ _(⁻) in deoxygenated methanol(15 mL) was added via syringe. The vessel was again purged with hydrogenthree times then pressurized to 65 psi and stirring commenced.Periodically, hydrogen was added to maintain the pressure between 50 to65 psi. Hydrogen uptake ceased after 4 hours. then after a further 1hour, the vessel was cooled to room temperature. The pressure wasreleased, the mixture was transferred to a flask, and the solvent wasremoved in vacuo to give the product. A small sample was removed andconverted to methyl (S)-3-cyano-5-methylhex-3-enoate by reaction withmethanol and 1N HCl. GC analysis showed >99% conversion 97.7% e.e. E.Potassium salt of 3-cyano-5-methylhexanoic acid generated in situ fromethyl 3-cyano-S-methylhex-3-enoate

Material MWt Quantity mmol Ethyl 3-cyano-5-methylhex-3-enoate 181.210.81 g 59.7 Potassium hydroxide 11.68 mL 58.4 [(R,R)-MeDuPHOS]Rh(COD)BF₄ ⁻ 604 18.0 mg 29.8 × 10⁻³ Methanol 32 120 mL Water 18 18 mL Hydrogen2 60 psi (4 bar)

[0062] A glass liner is charged with ethyl 3-cyano-5-methylhex-3-enoate(starting material prepared above), methanol (100 mL), and water (18mL). Potassium hydroxide is added with stirring. A liner is placed in a600 mL PARR hydrogenation vessel. The vessel is purged with nitrogen andthen with hydrogen via charging to 60 psi and releasing the pressure on5 cycles. The vessel is heated to 55° C. A solution of[(R,R)-MeDuPHOS]Rh(COD)⁺BF₄ ⁻ in deoxygenated methanol (18.0 mg in 20mL) is added via syringe. The vessel is again purged with hydrogen andthen pressurized to 60 psi with stirring. Periodically, hydrogen isadded to maintain the pressure between 50 to 60 psi. Hydrogen uptakeceases after 5 hours. After an additional 1 hour, the mixture is cooledto room temperature, and the pressure is released. The mixture istransferred to a flask, and the solvent is removed in vacuo to give theproduct. A small sample is removed and converted to(S)-3-cyano-5-methylhexanoic acid by reaction with 1N hydrochloric acid.GC analysis shows 98.7% conversion to the desired cyano alkanoic saltwith 96.6% e.e S isomer.

EXAMPLE 3

[0063] Hydrogenation of ethyl 3-cyano-5-methylhex-3-enoate

Material MWt Quantity mmol Ethyl 3-cyano-5-methylhex-3-enoate 181 0.36 g2.00 [(R,R)-Me-DuPHOS]Rh(COD) BF₄ ⁻ 604 1.2 mg 2 × 10⁻³ Methanol 5 mLHydrogen 60 psi (4 bar)

[0064] A. The reaction is carried out in a 50 mL micro reactor fittedwith an injection septum and valve. A micro reactor is used inconjunction with a glass liner. Methanol is deoxygenated by four cyclesof partial evacuation and refilling with nitrogen while stirring. Aliner charged with ethyl 3-cyano-5-methylhex-3-enoate D and a magneticstir bar is placed in the micro reactor. and the micro reactor issubsequently assembled. A hydrogen atmosphere is established by threecycles of charging the vessel with hydrogen and releasing the pressure.Methanol (4 mL) is added, and the vessel is then placed in an oil bathon a stirrer hotplate at 60° C. and allowed to come to thermalequilibrium (internal temp ˜45° C.). A small Schlenk tube is chargedwith [(RR)-Me-DuPHOS]Rh(COD)⁺BF₄ ⁻ and a nitrogen atmosphere establishedby four cycles of partial evacuation and refilling with nitrogen. Thecatalyst is dissolved in methanol such as to give a solution containing1.2 mg of catalyst in 1 mL of solvent. One milliliter of the catalystsolution is added via syringe to the micro reactor. The vessel is againpurged by pressurizing with hydrogen to 60 psi and releasing thepressure for a further four cycles. The vessel is then charged to 60 psiand is stirred until hydrogen uptake is judged to have ceased (˜3hours). The reactor is removed from the oil bath and allowed to cool.The pressure is then released and the solvent removed in vacuo. GCanalysis shows 99% conversion, 22.7% e.e. (R).

[0065] B. By following the general procedure of Example 3.1, 200 mg(1.190 mmol) of methyl 3-cyano-5-methyl-hex-3-enoate was dissolved in 3mL of methanol and reacted with hydrogen gas (60 psi) in the presence of43 mg (0.06 mmol) of [(R,R)-Et-DuPHOS]Rh(COD)⁺BF₄ ⁻ to afford 10%conversion to methyl 3-cyano-5-methylhexanoate having 33% e.e. (R).

EXAMPLE 4

[0066] Synthesis of Pregabalin

[0067] A. Conversion of Potassium Salt of (S)-3-cyano-5-methylhexanoicAcid to Pregabalin

[0068] The S-cyano acid, potassium salt (prepared as described inExample 2B, 94.9% S-isomer, 8.0 g, 41.4 mmol) is charged along withpotassium hydroxide (91% flake, 44.0 mg gross, 40.0 mg net, 0.7 mmol),water (15 mL), and 2B EtOH (i.e., denatured with toluene) (10 mL) to aPARR bottle containing sponge nickel catalyst (A-7000, Activated Metalsand Chemicals. Inc., P.O. Box 4130, Severville, Tenn. 37864, 5 g, waterwet). The slurry is shaken on a PARR shaker under 50 psi hydrogen atroom temperature overnight.

[0069] The slurry is filtered through a pad of Supercel. The filter cakeis rinsed with water (20 mL) and 2B EtOH (7 mL). The combined filtrateis mixed with glacial acetic acid (2.4 mL, 2.5 g, 41.6 mmol) and heatedat 70° C. for 30 minutes. The mixture is cooled to 0° C. and the solidis collected by filtration, washed with isopropanol (50 mL), and driedto give 3.2 g of product (20 mmol, 49% yield). HPLC assay of thematerial shows 99.7% (area under the curve) 3-isobutyl GABA. Enantiomeranalysis (HPLC) indicates the 3-isobutyl GABA as a mixture of isomers:97.82% is the desired S-isomer (pregabalin), and 2.18% is the undesiredR-isomer.

[0070] B. Conversion of tert-Butyl Ammonium Salt of(S)-3-cyano-5-methylhexanoic Acid to Pregabalin

[0071] The S-cyano acid, tert-butyl ammonium salt (prepared or describedin Example 2A, 97% S-isomer, 8.0 g, 35.0 mmol) is charged along withpotassium hydroxide (91% flake, 2.2 g gross, 2.0 g net, 35.6 mmol),water (15 mL), and 2B EtOH (II mL) to a PARR bottle containing spongenickel catalyst (A-7000, 5 g, water wet). The slurry is shaken on a PARRshaker under 50 psi hydrogen at room temperature overnight.

[0072] The slurry is filtered through a pad of Supercel. The filter cakeis rinsed with water (20 mL) and 2B EtOH (ethanol denatured withtoluene) (7 mL). The combined filtrate is charged with glacial aceticacid (4.1 mL, 4.3 g, 71.6 mmol). The resulting solution is heated to 70°C. and then allowed to cool slowly to room temperature. The reactionslurry is then stirred at 0° C. to 5° C. for 6 hours and filtered. Thesolid is rinsed with IPA (50 mL) and is dried for 2 days in a vacuumoven to give a solid weighing 3.4 g (61.0% overall yield). HPLC analysisidentifies the product as 97.20% (area) 3-isobutyl GABA, 99.92% of whichis the desired S-isomer (pregabalin).

[0073] An argon-purged 600 mL pressure reactor is charged tert-butylammonium 3-cyano-5-methylhex-3-enoate (prepared as described in Example1A 36 g, 159.1 mmol) and [(PR)MeDUPHOS]Rh(COD)BF₄ (0.054 g, 0.0894mmol). The reactor is pressure purged with argon (3×50 psi). To a 1000mL reactor is charged 360 mL of methanol. The methanol is pressurepurged with argon (3×50 psi). The methanol is then charged to thereactor containing the substrate and catalyst. The solution is pressurepurged with argon (3×50 psi), and then the reactor is pressurized to 50psi with hydrogen and stirred overnight at 27° C. to 33° C. The hydrogenpressure is released, and the solution purged with argon. The solutionis transferred into a vessel containing a solution of potassiumhydroxide (91%, 10.3 g, 167 mmol) in 90 mL of water. The solution isconcentrated to about 180 mL in vacuo. The concentrated solution istransferred to a 600 mL pressure reactor containing sponge nickel A-7000(12.0 g, 50% water wet). The solution is purged with argon (3×50 psi),and then the reactor is pressured to 50 psi with hydrogen and stirredovernight. The hydrogen pressure is released. The solution is purgedwith argon and filtered. The filter cake is washed with 90 mL ofmethanol. The filtrate is concentrated in vacuo to remove the methanol,and 72 mL of isopropyl alcohol is charged. The solution is heated to 65°C. Glacial acetic acid (9.4 mL, 171 mmol) is charged. and the solutionis heated to 73° C. The solution is quickly cooled to 50° C., thenslowly cooled to room temperature. The slurry is cooled to 0° C. to 5°C. for 3.5 hours. The slurry is filtered. and the cake is washed withisopropyl alcohol. The solid is dried under vacuum at 45° C. to give18.4 g (73%) of pregabalin as a white solid (99.89% S).

[0074] An argon-purged 170 L reactor is charged with tert-butyl ammonium3-cyano-5-methylhex-3-enoate (10 kg, 44.2 mol prepared as described inExample 1A) and [(R,R)MeDUPHOS]Rh(COD)BF₄ (0.015 kg, 0.0025 mol). Thereactor is pressure purged with argon (3×50 psi). To a 170 L still ischarged 100 L of methanol. The reactor is evacuated under vacuum. andthen the vacuum is broken with argon. The still is pressurized to 50 psiwith argon and then vented. This entire purge procedure is repeatedtwice more. The methanol is charged to the reactor containing thesubstrate and catalyst. The solution is pressure purged with argon (3×50psi), and then the vessel is pressurized to 50 psi with hydrogen andstirred overnight at 27° C. to 33° C. The hydrogen pressure is released.and the solution is purged with nitrogen. The solution is filtered intoa 170 L still containing a solution of potassium hydroxide (91%, 2.9 kg,46.4 mol) in 25 L of water. A 5 L wash of methanol is used to clean thetransfer line. The filtrate is concentrated to a volume of 50 to 60 L byvacuum distillation. This concentrated solution is transferred to a 170L reactor containing sponge nickel A-7000 (5.0 kg, 50% water wet). Thesolution is purged with nitrogen (3×50 psi). Then. the reactor ispressurized to 50 psi with hydrogen and stirred overnight. The hydrogenpressure is released, and the solution is purged with nitrogen. Thesolution is filtered into a 170 L still. and the filter and lines arerinsed with 30 L of methanol. The filtrate is concentrate by vacuumdistillation to a volume of 25 to 35 L, and then 30 L of isopropylalcohol is charged. The solution is concentrated by vacuum distillationto about 18 L. Isopropyl alcohol (20 L) and water (5 L) are charged, andthe solution is heated to 60° C. to 65° C. Glacial acetic acid (2.9 kg,47.7 mol) is charged. and the solution is heated to reflux. Water (8 L)is charged to make a solution. The solution is quickly cooled to 50° C.and then cooled to −5° C.±5° C. over about 5.5 hours. The slurry is heldat −5° C.±5° C. for about 10 hours and then filtered and washed withisopropyl alcohol (10 L). The solvent-wet filter cake is charged to a170 L still followed by water (20 L) and isopropyl alcohol (40 L). Theslurry is heated to reflux to make a clear solution. which is filteredinto a 170 L reactor. The solution is quickly cooled to 50° C. and thencooled to −5° C.±5° C. over about 3.5 hours. The slurry is held a −5°C.±5° C. for about 16 hours. The solid is filtered and washed withisopropyl alcohol (10 L). The solid is dried under vacuum at 45° C. for3 days to give 4.0 kg (57%) of pregabalin as a white solid (99.84% S).

EXAMPLE 5

[0075] Hydrogenation of 3-cyano-5-methylhex-3-enoic acid (free acid)

Material MWt Quantity mmol 3-Cyano-5-methylhex-3-enoic 153 200 mg 1.307acid [(S,S)-Me-BPE]Rh(COD)⁺BF₄ ⁻ 618.48 20 mg 0.0327 (2.5 mol %)Methanol 4 mL Hydrogen 50 psi (4 bar)

[0076] A. The free hexanoic acid was dissolved in methanol, and thechiral catalyst was added to the solution. The mixture was shaken at 24°C. for 19 hours under hydrogen at 50 psi. A sample was analyzed byproton NMR. and the reaction was determined to be 24% complete. with thecyano hexanoic acid having 95% e.e. (S).

[0077] One equivalent amount (0.18 mL) of triethylamine was added to thereaction mixture, and shaking was continued for 5 additional hours (24°C. 50 psi). The reaction mixture was filtered, and the solvent wasremoved by evaporation. The product was analyzed by proton NMR and shownto contain about 43% of the desired (S)-3-cyano-5-methylhexanoic acidhaving 95% e.e. for the S-enantiomer.

[0078] B. The above procedure was followed to react 250 mg (1.634 mmol)of 3-cyano-5-methylhex-3-enoic acid with hydrogen (50 psi) in thepresence of 8 mg (0.01634 mmol) of [(S,S)-Et-BPE]Rh(COD)⁺BF₄ ⁻ and 0.023mL (0.1634 mmol; 0.1 eq) of triethylamine in 5 mL of methanol at 24° C.for 40 hours. The reaction mixture was filtered, the solvent was removedby evaporation. and the product was shown by proton NMR to be 71%(S)-3-cyano-5-methylhexanoic acid with 84% e.e. for the S-enantiomer.

[0079] C. The above procedure was repeated. except that no base wasadded to the reaction mixture. The product was shown by proton NMR to be26%, (S)-3-cyano-5-methylhexanoic acid having 91% e.e. for theS-enantiomer.

[0080] D. The above procedure was followed to react 200 mg (1.307 mmol)of 3-cyano-5-methylhex-3-enoic acid with hydrogen (50 psi, 100 hours) inthe presence of 10 mg (0.01307 mmol) of [(S,S)-Et-DuPHOS]Rh(COD)⁺BF₄ ⁻.The product was shown by proton NMR to be 82%(S)-3-cyano-5-methylhexanoic acid having 56% e.e. for the S-enantiomer.

[0081] E. The procedure of Example 5D was repeated. except that 0.1 eq.(0.02 mL, 0.1307 mmol) of triethylamine was added to the reactivemixture. The reaction was stopped after 16 hours. and the product wasshown to be 86% (S)-3-cyano-5-methylhexanoic acid with 68% e.e. for theS-enantiomer.

[0082] F. The procedure of Example 5E was repeated. except that 1 eq.(0.18 mL, 1.307 mmol) of triethylamine was added to the reactionmixture. and the reaction was stopped at 16 hours. The product was shownby proton NMR to be 92% converted to (S)-3-cyano-S-methylhexanoic acidhaving 56% e.e. for the S-enantiomer.

[0083] G. By following the general procedures from above, 250 mg (1.634mmol) of 3-cyano-5-methylhex-3-enoic acid was reacted with hydrogen (50psi, 16 hours. 24° C.) in the presence of 12 mg (0.01634 mmol) of[(RR)-DIPAMP]Rh(COD)⁺BF₄ ⁻ in methanol (10 mL) to provide 51% of3-cyano-5-methylhexanoic acid having 72% e.e. for the R-enantiomer.

EXAMPLE 6

[0084] Recrystallization of Pregabalin

[0085] Pregabalin solid (117 kg, 735 mol) containing 0.6% of the(R)-enantiomer is combined with water (550 L; 4.7 L/kg pregabalin) andisopropyl alcohol (1100 L: 9.4 L/kg pregabalin). The mixture is heatedto dissolve the solids (about 75° C.±5° C.). filtered while hot, andcooled to 0° C.±5° C. to crystallize the product. The solid is collectedon a centrifuge and rinsed with isopropyl alcohol. The damp solid isdried under vacuum at 35° C. to 45° C. and then milled to give 91.8 kg(78.5%) of pregabalin as a white crystalline solid. The enantiomer ratiois 99.94% (S)-enantiomer pregabalin) and 0.06% of the (R)-enantiomer.

[0086] The invention and the manner and process of making and using it.are now described in such full. clear, concise, and exact terms as toenable any person skilled in the art to which it pertains, to make anduse the same. It is to be understood that the foregoing describespreferred embodiments of the present invention and that modificationsmay be made therein without departing from the spirit or scope of thepresent invention as set forth in the claims. To particularly point outand distinctly claim the subject matter regarded as the invention, thefollowing claims conclude this specification.

What is claimed is:
 1. A method for preparing an (S)-3-cyano-5-methylhexanoic acid derivative of the formula

wherein X is CO₂H or CO₂—Y. and where Y is a cation; the method comprising asymmetric catalytic hydrogenation of an alkene of the formula

in the presence of a chiral catalyst.
 2. A method according to claim 1 wherein X is CO₂—Y.
 3. A method according to claim 1, wherein the chiral catalyst is a rhodium complex of an (R,R)-DuPHOS ligand. the ligand having the formula

wherein R is alkyl.
 4. A method according to claim 3, wherein the chiral catalyst is [Rh(ligand)(COD)]BF₄.
 5. A method according to claim 3, wherein R is methyl or ethyl.
 6. A method according to claim 1, wherein the alkene is the E isomer or the Z isomer or is a mixture of said geometric isomers.
 7. A method according to claim 1, wherein the cation is an alkali metal or alkaline earth metal.
 8. A method according to claim 7, wherein the alkali metal is potassium.
 9. A method according to claim 1, wherein the cation is a salt of a primary amine or a salt of secondary amine.
 10. A method according to claim 9, wherein the amine is tert-butylamine.
 11. A method according to claim 1, which further comprises first convening a carboxylic ester of the formula

wherein R¹ is alkyl to the carboxylate salt of the formula

where Y is a cation.
 12. A method according to claim 11, wherein R¹ is ethyl.
 13. A method according to claim 11, wherein the carboxylate salt is isolated prior to hydrogenation.
 14. A method according to claim 11, wherein the carboxylate salt is prepared in situ prior to hydrogenation.
 15. A method according to claim
 8. further comprising acidifying the (S)-3-cyano-5-methylhexanoic acid carboxylate salt to form (S)-3-cyano-5-methylhexanoic acid.
 16. A compound of the formula

wherein X is CO₂H or CO₂—Y, and where Y is a cation.
 17. A compound of the formula

wherein R¹ is alkyl.
 18. A method for preparing a compound of the formula

wherein R¹ is alkyl the method comprising asymmetric catalytic hydrogenation of an alkene of the formula

in the presence of a chiral catalyst.
 19. A method according to claim 18, wherein the chiral catalyst is a rhodium complex of an (S,S)-DuPHOS ligand, the ligand having the formula

wherein R is alkyl.
 20. A method according to claim 19, wherein the chiral catalyst is [Rh(ligand)(COD)]BF₄.
 21. A method according to claim 19, wherein R is methyl or ethyl.
 22. A method according to claim 21 wherein R¹ is ethyl.
 23. A method according to claim 1 wherein the cation Y is selected from the group consisting of H⁺, the salt formed by reaction with a protonated primary or secondary amine, an alkaline earth metal, and an alkali metal.
 24. A compound of the formula

wherein Y is a cation.
 25. A method according to claim 1 which further comprises the reduction of the cyano group to form an amino group, and when Y is other than H⁺, protonation by reaction with an acid to produce pregabalin.
 26. A process for preparing pregabalin comprising asymmetrically hydrogenating

where Y is a cation, in the presence of a chiral catalyst, followed by reduction of the cyano group, and protonation to the free acid. 